Iron metabolism has the particularity that it is controlled by absorption rather than by excretion: iron is eliminated mainly by means of the loss of cells of the mucosae and of the skin (approximately 1 mg per day). The total pool of iron in our body is approximately 4,000 mg, of which a little over 2,000 is in erythrocytes and in their precursors and 1,600-1,800 mg are in the form of deposit, while the amount of iron that can be found in serum is approximately 4 mg.
Lack of iron or hyposideremia, due often that not only to its malabsorption at the intestinal level, is one of the greatest causes of the forms of anemia that develop in children or adults. It is calculated that approximately 750 million people worldwide (Umbreit J., Am. J. Hematol. 2005; 78:225-231; Killip S., Bennet J. M., Chambers M. D., Am. Fam. Physician 2007; 75:671-678) are affected by this nutritional deficiency, particularly children, in which the iron deficiency can cause severe cognitive deficits, or in fertile or pregnant women, in which iron deficiency can cause premature birth and prenatal mortality. This deficiency is usually treated by administering divalent or trivalent iron. Divalent iron, in the form of salts or complexes, is administered generally orally (i.e., for absorption at the gastrointestinal level), while trivalent iron is administered only in the form of a complex both orally (i.e., for adsorption at the gastrointestinal level) and parenterally.
Therapy with Divalent Iron
Oral anti-hyposideremia therapy (i.e., for absorption at the gastrointestinal level) with salts or complexes of divalent iron (i.e., Fe(II), Fe2+ or Fe++), despite being normally effective, is characterized by some side effects that can limit its use severely. The oral administration of ferrous sulfate, ferrous ascorbate or other salts/complexes such as ferrous gluconate or citrate has as a first negative effect intolerance at the gastric level, which causes nausea, vomiting, epigastric pain such as to often encounter refusal of the therapy by the patient. Moreover, susceptibility to oxidation in the bowel portion of the duodenum-jejunum of divalent iron (in a neutral-basic environment, the most stable oxidation state of iron is the trivalent one) causes a drastic decrease in absorption, which is compensated by an increase in doses, which in turn increase the negative effects at the gastric level and not only. This leads in fact to another drawback, which is even more severe, i.e., toxicity at the systemic level. The maximum dose of divalent iron that can be administered orally in the therapy of sideropenic anemia, particularly of chronic sideropenic anemia, especially if applied for an extended time interval, for example two weeks to six months, oscillates between 150 and 450 mg per day for a human patient, depending on the severity of the disease and on the type of preparation used. The absorbed iron is usually carried and deposited in iron-deficient cells by protein (transferrin is one of the main iron carriers); however, if the quantity of iron absorbed is such as to saturate transferrin (or if absorption is faster than the complexing rate of transferrin) and is such as to circulate in ionized form in the blood as trivalent iron, toxicity conditions can occur. This non transferrin bound excess (so-called free iron or “NTBI”—non transferrin bound iron) manifests its toxicity by causing the formation of compounds based on reactive oxygen, such as the superoxide anion (O2-), hydrogen peroxide (H2O2) or the hydroxyl radical (OH.), all of which are capable of damaging cells by oxidizing protein, lipids and DNA itself (Gutteridge J. M. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin. Chem. 1995; 41:1819-1828; Stadtman E. R., Berlett B. S. Reactive oxygen-mediated protein oxidation in aging and disease. Chem. Res. Toxicol. 1997; 10:485-494; Dean R. T., Fu S., Stocker R. et al. Biochemistry and pathology of radical-mediated protein oxidation. Biochem. J. 1997; 324 (Pt 1): 1-18; Henle E. S., Linn S. Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide. J. Biol. Chem. 1997; 272:19095-19098; Toyokuni S. Iron and carcinogenesis: from Fenton reaction to target genes. Redox Rep. 2002; 7: 189-197).
This toxicity of divalent iron can occur both in the adult and in the child, in which the outcome can even be fatal.
In these cases, therefore, the patient rapidly reaches a level of serum iron that is higher than desired, entering a state of hypersideremia; in these conditions, the patient is exposed to an oxidative stress which is due to high blood levels of iron [Al-Rashid, Rashid A, (1971) Clinical Toxicology, 4:4, 571-578; Witzleben C. L. and Buck B. E. (1971) Clinical Toxicology 4:4, 579-583; K. R. Reissmann and T. J. Coleman, (1955) 10: 46-51]. Through the years there has been an important number of deaths due to hypersideremia in children after oral administration of iron sulfate or other divalent iron salts. Regrettably, these deaths have demonstrated that the definition of the therapeutic window for oral administration of divalent iron entails considerable difficulties (Reissmann K. R, Coleman T. J, Budai B. S. and L. R. Moriarty, (1955) 10:35-45; Editorial: Acute iron poisoning in children. Canad. M. A. J. 66: 278, 1952.; Swift, S. C., Cefalu, V., and Rubell, E. B.: Ferrous sulfate poisoning J. Pediat. 40: 6, 1952; Duffy, T. L., and Diehl, A. M.: Ferrous sulfate poisoning. J. Pediat. 40: 1, 1952). Part of the toxicity of the Fe++ administered orally is attributed in many publications to its direct action on intestinal mucosa, which is necrotized, with severe hemorrhagic events (Spencer, I. O. B.: Ferrous sulfate poisoning in children. Brit. M. J. 2: 1112, 1951).
Therapy with Trivalent Iron
Trivalent iron (i.e., Fe(III), Fe3+ or Fe+++), differently from reduced iron, can be absorbed only at extremely acid pH levels, distinctly lower than 2.0, since only in these conditions is it stable as a cation and does not precipitate. For this reason, oral administration (i.e., for absorption at the gastrointestinal level) of trivalent iron salts finds no application, since the pH close to neutrality of the duodenum-jejunum intestinal tract, which is the portion assigned to iron absorption, causes its precipitation, making its absorption impossible. Oral administration of trivalent Fe has instead been made possible by using complexing agents such as citrate anions, EDTA and others—or mono and disaccharides, which are able, again by complexing, to render soluble even trivalent Fe in the form of hydroxide oxide (FeOOH). Therefore, in these conditions the trivalent iron contained in the complexes cited above, by not precipitating at the level of the duodenum-jejunum tract, remains bioavailable for gastrointestinal absorption and is therefore usable for oral administration.
Moreover, these Fe+++ complexes, administered orally, do not produce the side effects of Fe++ salts.
However, the drawback observed in the development of these complexes is associated with the difficulty in studying their pharmacokinetics in healthy volunteers. It would appear in fact that the extent of the absorption of these compounds depends on the need of said individual to increase iron levels (W. Forth and S. G. Schäfer, Arzneim.-Forsch./Drug. Res. 37(I), Nr 1a: 96-99 (1987); P. Geisser and A. Müller, Arzneim.-Forsch./Drug. Res. 37(I), Nr 1a: 100-104 (1987); P. Geisser and A. Müller, Arzneim.-Forsch./Drug. Res. 34(II), Nr 11: 1560-1569 (1984); W. Schneider, Arzneim.-Forsch./Drug. Res. 37(I), Nr 1a: 92-95 (1987); P. Jacobs, Arzneim.-Forsch./Drug. Res. 37(I), Nr 1a: 113-116 (1987); E. Werner and J. P. Kaltwasser, Arzneim.-Forsch./Drug. Res. 37(I), Nr 1a: 116-121 (1987)).
The results obtained with studies conducted on anemic patients would appear to show that serum iron levels observed following oral administration of ferrous sulfate or iron oxide hydroxide that has been complexed (for example with a maltodextrin) are entirely comparable. The subject is in any case still at the center of a debate, since the various pharmacokinetics that have been performed with unmarked trivalent iron complexes taken orally have yielded ambiguous results. This may be due also to the fact that complexes of ferro-maltodextrin (so-called ferric polymaltose) obtained with different synthetic methods have shown different stability and chemical-physical characteristics; the data obtained in pharmacokinetics studies therefore are not often comparable. Of the Fe+++ complexes studied for their use in oral therapy, only ferric polymaltose is currently commercially available.
Having therefore evaluated the negative aspects associated with the oral administration of compounds based on divalent and trivalent Fe, it has been thought to use another modus of administration capable of bypassing the digestive system without however resorting to the parenteral pathway. This is done to allow easy anti-anemic therapy even for patients affected for example by inflammatory bowel diseases (for example IBD or celiac disease) without however resorting to the intravenous pathway, which is more expensive and is characterized by important side effects.
The literature reports various attempts to allow administration of various substances, including iron, by means of a pathway that is different from the gastrointestinal or parenteral one. However, as regards therapy of hyposideremia, the drugs currently commercially available are preset for the oral pathway or for the parenteral pathway.
In view of what has been described above, it appears therefore evident that currently there are no formulations of iron for treatment, preferably prolonged treatment, of hyposideremia or of its most severe states, such as malabsorption of iron due to celiac disease or chronic inflammatory bowel diseases, or sideropenic anemia due to blood losses, which are easy to manage and are not associated with important unwanted effects.
The present disclosure therefore provides compounds of iron and new formulations of iron that are not parenteral and allow an alternative to classic oral, i.e., gastrointestinal, administration, in the therapy of hyposideremia or of its more severe states, avoiding advantageously the drawbacks associated with gastrointestinal administration of salts of divalent Fe or of complexes of trivalent iron. By means of the development of these formulations, facilitated treatment also becomes possible of anemic states in patients that do not tolerate oral therapy (i.e., by absorption at the gastrointestinal level), such as for example patients affected by chronic inflammatory bowel diseases (IBD) or by celiac disease, thus avoiding parenteral therapy.
The present disclosure further provides new formulations of iron that are not parenteral and exhibit a reduced toxicity with respect to classic formulations of divalent iron that are administered orally.
The present disclosure also provides new formulations of divalent iron that are effective for the therapy of anemic states due to malabsorption of iron caused by celiac disease or chronic inflammatory bowel diseases or due to chronic sideropenic anemia caused by blood losses at lower dosage regimens than oral preparations (i.e., with gastrointestinal absorption) that are currently commercially available, thus lowering favorably the risk/benefit ratio of the therapy.